HIV-Induced Immune Activation in Humanized MIce

HIV 诱导的人源化小鼠免疫激活

• 批准号: 8599092
• 负责人: MANJUNATH NARASIMHA SWAMY
• 金额: $ 17.74万
• 依托单位: TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-16 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8599092
• 关键词: Arginine; Bacterial Translocation; Binding; Blood Circulation; CD4 Positive T Lymphocytes; Cholinergic Receptors; Chronic; Cytokine Activation; Dendritic Cells; Dengue Virus; Disease; Disease Progression; HIV; HIV Infections; HMGB1 gene; Human; IL8 gene; Immune; Immune System Diseases; Immune response; Individual; Infection; Inflammation Mediators; Inflammatory; Interleukin-6; Intestines; Ligands; Lymphocyte; Mediating; Mucous Membrane; Mus; Nucleic Acids; Peptides; Phenotype; Reporting; Risk; Role; Sepsis; Serum; Small Interfering RNA; T-Lymphocyte; TNF gene; Testing; Toll-like receptors; Viral; Viral Load result; Viral Proteins; Viremia; apoptosis in lymphocytes; base; cell type; cytokine; immune activation; in vivo; macrophage; microbial; monocyte; mortality; mouse model; public health relevance; rabies virus glycoprotein G; receptor for advanced glycation endproducts; targeted delivery; toll-like receptor 4

DESCRIPTION (provided by applicant): Persistent immune activation is a strong predictor of disease progression in HIV infection and is characterized by activation of all immune cell types, increased levels of proinflammatory cytokines and activation-induced lymphocyte apoptosis. Translocation of microbial toll-like receptor (TLR) ligands from the gut to the systemic circulatio has been recognized in recent years to be a major factor in inducing immune activation. The resulting increase in inflammatory cytokines may be the fundamental cause for immune activation and determinant of disease progression. The cytokine storm, immune activation and lymphocyte apoptosis attended with microbial products in systemic circulation seen in HIV infection also characterizes natural and experimental sepsis. HMGB1 secreted from macrophages and dendritic cells acts as a master regulator of cytokine storm in sepsis. We have recently shown that silencing HMGB1 in human macrophages and dendritic cells in vivo in humanized BLT mice by targeted delivery of siRNA (via a peptide called RVG-9R) dramatically suppressed the sepsis-induced cytokine storm and mortality. Although serum level of HMGB1 as well as downstream cytokines are also elevated in HIV infected individuals, their role in chronic immune activation is not clear. In this proposal, we will test the role of HMGB1 and downstream cytokines, their relation to microbial products and the effect of suppressing these inflammatory mediators on immune activation and disease progression in vivo using the humanized mouse model for HIV infection. In Aim 1, we will characterize the full spectrum of immune activation in HIV infected humanized mice without or with ART. In the second aim we will test if silencing HMGB1 or downstream cytokines by targeted delivery of siRNA to macrophages and dendritic cells can reduce immune activation and disease progression in infected mice.

描述（由申请人提供）：持续的免疫激活是 HIV 感染疾病进展的有力预测因素，其特征是所有免疫细胞类型的激活、促炎细胞因子水平增加以及激活诱导的淋巴细胞凋亡。近年来，微生物 Toll 样受体 (TLR) 配体从肠道易位至全身循环已被认为是诱导免疫激活的主要因素。由此产生的炎症细胞因子的增加可能是免疫激活的根本原因和疾病进展的决定因素。 HIV感染中观察到的细胞因子风暴、免疫激活和淋巴细胞凋亡以及体循环中的微生物产物伴随着自然和实验性脓毒症的特征。巨噬细胞和树突状细胞分泌的 HMGB1 是脓毒症细胞因子风暴的主要调节因子。我们最近发现，通过靶向递送 siRNA（通过一种名为 RVG-9R 的肽），在人源化 BLT 小鼠体内沉默人巨噬细胞和树突状细胞中的 HMGB1，可显着抑制脓毒症引起的细胞因子风暴和死亡率。尽管 HIV 感染者的血清 HMGB1 及下游细胞因子水平也升高，但它们在慢性免疫激活中的作用尚不清楚。 在本提案中，我们将使用 HIV 感染的人源化小鼠模型来测试 HMGB1 和下游细胞因子的作用、它们与微生物产物的关系以及抑制这些炎症介质对体内免疫激活和疾病进展的影响。在目标 1 中，我们将描述在没有或有 ART 的情况下感染 HIV 的人源化小鼠的全谱免疫激活。在第二个目标中，我们将测试通过将 siRNA 靶向递送至巨噬细胞和树突状细胞来沉默 HMGB1 或下游细胞因子是否可以减少受感染小鼠的免疫激活和疾病进展。